Disinfecting and sterilizing concentrate containing and aromatic dialdehyde and a neutral pH buffering system

ABSTRACT

A disinfecting and sterilizing concentrate containing an aromatic dialdehyde and a neutral pH buffering system is provided. Aromatic dialdehyde concentrations of greater than 5 w/w % are achieved while maintaining the stability of the buffering system. A method and a kit for preparing a disinfecting and sterilizing concentrate is also provided.

This application is a continuation of U.S. application Ser. No.09/010,351, filed Jan. 21, 1998 now U.S. Pat. No. 5,936,001.

BACKGROUND OF THE INVENTION

1. Field of Invention

The present invention relates to disinfecting and sterilizing solutions,and more particularly to a disinfecting and sterilizing concentratecontaining an aromatic dialdehyde and a neutral pH buffering system.

2. Description of Prior Art

Aromatic dialdehyde disinfecting and sterilizing solutions are wellknown in the art. Aromatic dialdehyde solutions have bacteriostatic andfungistatic activity. They are useful for disinfecting or sterilizingmedical devices or environmental surfaces. Unfortunately, presentaromatic dialdehyde solutions limit the concentration of the aromaticsolution to less than or equal to 5 w/w % of the total solution becausearomatic dialdehydes have limited aqueous solubility. Whilewater-miscible solvents may increase the solubility of aromaticdialdehyde, the solvents adversely affect the buffering systems ofaromatic dialdehyde disinfecting and sterilizing solutions.

Bruckner et al. in U.S. Pat. No. 4,971,999, discuss ortho-phthalaldehydeas the active ingredient in an aromatic dialdehyde disinfecting andsterilizing solution. U.S. Pat. No. 4,971,999 is incorporated herein byreference. They discuss "in-use solutions" and more concentratedsolutions. An "in-use solution" contains an effective amount of theactive aromatic dialdehyde ingredient and is a solution which issufficiently dilute for ordinary disinfecting and sterilizing purposes.

Bruckner et al. observe that for "in-use solutions,"ortho-phthalaldehyde is normally present in amounts between 0.025 w/w %and 1 w/w %. They also observe that higher concentrations, e.g., up to 2w/w %, can be used but that the preferred concentration is 0.05 w/w % to0.5 w/w %. They further observe that higher concentrations may be usedfor shipping the solution to the point of use and the solution can thenbe diluted with water to the desired "in-use solution" concentration.

In any event, they note that the limit on the amount ofortho-phthalaldehyde used in the concentrate solution is a function ofthe solubility of the aromatic dialdehyde in water, which is about 5 w/w%. Bruckner et al. indicate that the concentration may be increasedabove the 5 w/w % level with the addition of water-miscible solvents.They specifically state that suitable solvents include methanol,ethanol, isopropanol, glycols, tetrahydrofuran, dimethyl sulfoxide, anddioxane. But, Bruckner et al. do not discuss or address any adverseaffects caused by the additional solvents. There are some adverseaffects.

Bruckner et al. observe that an alkalinating or acidifying salt can beused in the compositions (solutions) as a buffer to maintain a desiredcomposition pH during storage and use. Bruckner specifically disclosesan alkali metal carbonate or bicarbonate, e.g., sodium bicarbonate orpotassium bicarbonate, or phosphate as a buffering salt. They note thatthe buffer may be an organic carboxylate salt such as sodium citrate,sodium acetate, potassium hydrogen phthalate, potassium citrate, orpotassium acetate, or an inorganic borate salt such as potassium orsodium borate.

While Bruckner et al. contend that the disinfecting properties of thecomposition are not pH dependent, they do note that the sporicidalactivity of an aromatic dialdehyde solution is somewhat pH dependent.They specifically observe this pH dependency at low aromatic aldehydeconcentrations (e.g., 0.5 w/w % or less for phthaladehyde). They reportthat the optimal pH range for sporicidal activity is between 6 and 8 andthereby underscore the importance of buffering.

Moreover, the pH range from about 6 up to about 8 is preferred to ensurematerials compatibility of certain medical instruments or utensils.Certain medical instruments or utensils are prepared from materials suchas anodized aluminum, carbon steel, and rubber. These materials arechemically incompatible with environments outside the pH range fromabout 6 up to about 8. Therefore, to prevent harm to medical instrumentsor utensils prepared from these materials, a buffering system isrequired to maintain a pH in the range from about 6 up to about 8.

Unfortunately, the concentration of water-miscible solvents required toincrease the concentration of the aromatic dialdehyde above 5 w/w % aregenerally incompatible with the buffering system of the aromaticdialdehyde solutions. That is, as the concentration of the aromaticdialdehyde is increased by the addition of water-miscible solvents, thephysical stability of the buffering system is diminished. This physicalinstability is particularly apparent with phosphate buffering systems.To achieve and maintain the desired pH range from about 6 to about 8,the concentration of the buffering system must be increased as theconcentration of aromatic dialdehyde is increased. Accordingly, there isa need to increase the concentration of the aromatic dialdehyde and theconcentration of the pH buffering system while maintaining the physicalstability of the pH buffering system. In other words, there is a need tostabilize the buffering systems of concentrated aromatic dialdehydesolutions against the water-miscible solvents used to increase theconcentration of the aromatic dialdehyde. Throughout the entire process,there is, of course, a need to ensure the chemical stability of thearomatic dialdehyde.

SUMMARY OF THE INVENTION

According to the present invention, a disinfecting and sterilizingconcentrate containing an aromatic dialdehyde and a neutral pH bufferingsystem is provided. More specifically, there is provided a disinfectingand sterilizing concentrate comprising an aromatic dialdehyde present ina concentration greater than 5 w/w %, a water miscible solvent, and a pHbuffering salt. Concentrations of greater than 5 w/w % are achievedwhile maintaining the physical stability of the pH buffering system. Amethod and a kit for preparing a disinfecting and sterilizingconcentrate is also provided. Further, a reduction of the amount ofwaste materials is achieved by reducing the amount of packaging requiredto deliver aromatic dialdehyde disinfecting and sterilizing solutions.

DESCRIPTION OF THE INVENTION

A disinfecting and sterilizing concentrate comprising an aromaticdialdehyde present a concentration greater than 5 w/w %, a watermiscible solvent, and a pH buffering salt is provided. The concentratemay additionally contain a stabilizer, water, and minor ingredients. Thewater-miscible solvent increases the solubility of the aromaticdialdehyde. The pH buffering salt maintains the pH of the "in usesolution." The stabilizer protects the pH buffering salt from theharmful effects of the water-miscible solvent.

The aromatic dialdehydes useful in the present invention preferably havethe formula: ##STR1## and are commonly called: ortho-phthalaldehyde,where X is CHO and Y and Z are H,

isophthalaldehyde, where Y is CHO and X and Z are H, and

terephthalaldehyde, where Z is CHO and X and Y are H.

The preferred aromatic dialdehyde is ortho-phthalaldehyde because of itsgood solubility in water and disinfecting and sterilizing activity. Thearomatic dialdehyde is present in an "in-use solution" concentration inan amount ranging from about 0.025 w/w % and 1 w/w %. A preferredconcentration ranges from about 0.05 w/w % to about 0.6 w/w %.

Suitable water-miscible solvents include solvents having either ahydroxy or carbonyl group (such as ethanol, methanol, 1,4-butanediol,ethylene glycol, propylene glycol, isopropanol, acetone, and polyols),dimethylsulfoxide, dioxane, and tetrahydrofuran. Solvents with lowerhuman toxicity are preferable and include ethanol, 1,4-butanediol, andpropylene glycol.

Suitable buffering salts for maintaining a pH range from about 6 toabout 8 include boric acid/sodium borate, maleic acid/sodium maleate,monobasic phosphate/dibasic phosphate, and citric acid/sodium citrate.Other buffering salts can achieve the desired pH range, but bufferingsalts with lower human toxicity are preferable. For example, cacodylateand sodium barbital are buffering salts that can achieve the desired pH,but these salts would not prove useful because they pose human toxicityproblems. The identified buffering salts are preferred in this order:(1) monobasic phosphate/dibasic phosphate, (2) citric acid/sodiumcitrate, (3) boric acid/sodium borate, and (4) maleic acid/sodiummaleate.

It should be noted that aromatic dialdehydes are also incompatible withbuffering systems having primary or secondary amines. Notably, aromaticdialdehydes cross-link primary or secondary amine buffering systems andthereby reduce the concentration of both the aromatic dialdehyde and thebuffering systems. For example, tris(hydroxymethyl) aminomethane and2-amino-2-methyl-1,3-propanediol are amines that can cross-link in thepresence of an aromatic dialdehyde.

Suitable stabilizers to protect the buffering salts against the adverseeffects of the water-miscible solvents include polyols (such as glyceroland sorbitol) and propylene carbonate. The physical stability of thebuffering salt is defined as no formation of precipitates or phaseseparation of the buffered solution at 4° C. for a minimum of 2 weeksand is determined by visual inspection. The chemical stability of thearomatic dialdehyde is defined as no loss of the aromatic dialdehyde inexcess of 15% of the total amount initially present at 40° C. for aminimum of sixty (60) days and is determined by high performance liquidchromatography.

Suitable minor ingredients include dyes, chelants [e.g.,ethylenediaminetetraacetic acid (EDTA), citric acid], and builders[e.g., sodium tripolyphosphate (STPP), other phosphonates]. The use ofminor ingredients is well known to those of ordinary skill in the artand does not affect the active ingredients of the solutions orsolutions' performance.

The relationship between the solvent/stabilizer and the buffering saltsaffects the choice of buffering salt. Notably, phosphate bufferingsystems are more sensitive to alcohol (solvent) concentrations ascompared to borate or maleate buffering systems. Because maleatebuffering systems are not as sensitive to alcohol concentrations asother buffering systems, lower concentrations of stabilizers areappropriate. In fact, a stabilizer may be an unnecessary ingredient forcertain concentrate formulations containing a maleate buffering systems.It should also be noted that some buffering systems are insoluble inalcohols and diols, for example, phosphate buffering systems areinsoluble in alcohol.

In an embodiment of the invention, a formulation of the concentrate isrepresented as:

    ______________________________________                                        Ingredient       Weight Percent (w/w %)                                       ______________________________________                                        Aromatic Dialdehyde                                                                            5-30                                                         Solvent          1-60                                                         Buffer Salts     0.5-25                                                       Stabilizer       0-50                                                         Water & Minor Ingredients                                                                      remainder                                                    ______________________________________                                    

In a preferred embodiment of the invention, a formulation of theconcentrate is represented as:

    ______________________________________                                        Ingredient       Weight Percent (w/w %)                                       ______________________________________                                        Aromatic Dialdehyde                                                                            5-25                                                         Solvent          5-50                                                         Buffer Salts     1-20                                                         Stabilizer       0-45                                                         Water & Minor Ingredients                                                                      remainder                                                    ______________________________________                                    

In a more preferred embodiment of the invention, a formulation of theconcentrate is represented as:

    ______________________________________                                        Ingredient       Weight Percent (w/w %)                                       ______________________________________                                        Aromatic Dialdehyde                                                                            10-20                                                        Solvent          10-45                                                        Buffer Salts      1-15                                                        Stabilizer        0-40                                                        Water & Minor Ingredients                                                                      remainder                                                    ______________________________________                                    

The order of addition affects the formulation time. Preferably and toreduce formulation time, the water-miscible solvent and the water arefirst mixed together. Next, the stabilizer is admixed. Next, the buffersalt is admixed. Next, the aromatic dialdehyde is admixed to thesolution. Finally, the minor ingredients are admixed. The order ofaddition affects formulation time for at least two reasons. If thearomatic dialdehyde is added directly to the water, the aromaticdialdehyde becomes hydrated. As a hydrate, the aromatic dialdehydedissolves more slowly in the water-miscible solvent. Accordingly, it isdesirable to avoid hydration of the aromatic dialdehyde. Because therate of dissolution and the stability of the aromatic dialdehyde issomewhat pH dependent, addition of the aromatic dialdehyde shouldpreferably follow the addition of the buffering salt. Notably, thearomatic dialdehyde dissolves more slower in low pH solutions than itdoes in neutral pH solutions. Also, if dissolved into solutions having apH above neutral, the aromatic dialdehyde is more likely to polymerizethan it is in solutions having a neutral pH. Additionally, the boricacid buffering system will dissolve more quickly in the stabilizerglycerol if the glycerol is heated. However, when using volatilesolvents, such as ethanol, the heating of the formulation is controlledto minimize evaporation losses.

An Alternate Embodiment

In an alternate embodiment, a kit for preparing a disinfecting andsterilizing concentrate is provided. In the kit, the concentratedaromatic dialdehyde and the buffering system are maintained as twodistinct solutions, as they are separately packaged, for example, in asingle split-chamber bottle. The split-chamber bottle provides for asingle dosing method. In this embodiment, the second solution may bephysically or chemically incompatible with the first solution. Thisembodiment is particularly useful with phosphate buffering systemsbecause phosphate buffering systems are particularly sensitive toalcohol (solvent) concentrations.

In this alternate embodiment, a formulation for the kit is representedas:

    ______________________________________                                        Solution for Chamber 1                                                                         Solution for Chamber 2                                       Ingredient                                                                             Weight Percent*                                                                           Ingredient Weight Percent*                               ______________________________________                                        Aromatic 5-60        Buffering Salt                                                                           1-50                                          Dialdehyde                                                                    Solvent  2-70        Water & Minor                                                                            remainder                                                          Ingredients                                              Water    remainder                                                            ______________________________________                                         *Weight percent is weightby-weight percent (w/w %).                      

In a preferred alternate embodiment, a formulation for the kit isrepresented as:

    ______________________________________                                        Solution for Chamber 1                                                                         Solution for Chamber 2                                       Ingredient                                                                             Weight Percent                                                                            Ingredient  Weight Percent                               ______________________________________                                        Aromatic 10-50       Buffering Salt                                                                            2-40                                         Dialdehyde                                                                    Solvent  10-50       Water & Minor                                                                             remainder                                                         Ingredients                                              Water    remainder                                                            ______________________________________                                    

In a more preferred alternate embodiment, a formulation for the kit isrepresented as:

    ______________________________________                                        Solution for Chamber 1                                                                         Solution for Chamber 2                                       Ingredient                                                                             Weight Percent                                                                            Ingredient  Weight Percent                               ______________________________________                                        Aromatic 20-40       Buffering Salt                                                                            2-30                                         Dialdehyde                                                                    Solvent  20-50       Water & Minor                                                                             remainder                                                         Ingredients                                              Water    remainder                                                            ______________________________________                                    

In the alternate embodiment, the minor ingredients may be added toSolution 1, Solution 2, or both. Adding the minor ingredients toSolution 2 is preferable because it avoids any potential interactionbetween the minor ingredients and the aromatic dialdehyde of Solution 1.Also, a stabilizer is unnecessary in the alternate embodiment becausethe buffering system and the water-miscible solvent are not combineduntil just prior to use and at "in-use solution" concentrations.Moreover, Solution 1 and Solution 2 of the kit may be combined invarious ratios, for example, 3:1, 2:1, 1:1, 1:2, and 1:3, respectively.The preferred ratio is 1:1.

EXAMPLES

The following formulations exemplify the more preferred embodiment andthe more preferred alternate embodiment. The formulations are at 24Xconcentrates, where X is the "in-use solution" concentration. It isunderstood that the following examples are provided to furtherillustrate the invention. They do not in anyway limit the scope of thepresent invention.

Example #1

In this example, a concentrate having the following formulation wasprepared:

    ______________________________________                                        Ingredient     Weight Percent (w/w %)                                         ______________________________________                                        ortho-phthalaldehyde                                                                         11.5                                                           ethanol        19.5                                                           boric acid      5.8                                                           borax           3.5                                                           glycerol       39.0                                                           water          19.5                                                           minor ingredients                                                                             1.2                                                           ______________________________________                                    

This formulation was prepared by first mixing the ethanol and watertogether. Next, the glycerol was added. The composition was then heatedbecause the borate buffering system dissolves more quickly at highertemperatures. The boric acid and borax ingredients were then added. Theresulting composition was then cooled to prevent evaporation of theethanol. The ortho-phthalaldehyde was then added to the mixture. Theminor ingredients including 0.5 w/w % of a 1% dye in water solution, 0.5w/w % of 1% calcium sequestrant (EDTA) in water solution, and 0.2 w/w %of a copper sequestrant (benzotriazole) were then added.

Evidence of pH Buffering

An "in-use solution" of the concentrate was prepared by diluting theconcentrate 24 times. The "in-use solution" has a pH of 7.5. Thesolution's pH decreases by only 0.3 units when the "in-use solution" isdiluted by half with water. The solution's pH decreases by only 0.3units per mL of 0.1 N HCl added to the "in-use solution."

Example #2

In this example, a concentrate having the following formulation wasprepared:

    ______________________________________                                        Ingredient     Weight Percent (w/w %)                                         ______________________________________                                        ortho-phthalaldehyde                                                                         11.0                                                           1,4-butanediol 37.6                                                           maleic acid     7.5                                                           sodium hydroxide                                                                              5.3                                                           water          37.6                                                           minor ingredients                                                                             1.0                                                           ______________________________________                                    

This formulation was prepared by first adding the sodium hydroxide tothe water. The resulting solution was cooled. Next, the maleic acid wasadded. The solution was again cooled. Next, the 1,4-butanediol wasadmixed. Then, the ortho-phthalaldehyde was admixed. The minoringredients including 0.5 w/w % of a 1% dye in water solution and 0.5w/w % of 1% calcium sequestrant (namely, EDTA) in water solution werefinally added.

Because this concentrate contained a maleate buffering system, thebuffering system did not require a stabilizer against the water-misciblesolvent, 1,4-butanediol. Maleate buffering systems are not particularlysensitive to solvent concentration up to 24X concentrates. Ifconcentrates of 30X or greater are desired, a stabilizer is preferablyadded to protect the physical stability of the maleate buffering system.

Evidence of pH Buffering

An "in-use solution" of the concentrate was prepared by diluting theconcentrate 24 times. The "in-use solution" has a pH of 7.2. Thesolution's pH decreases by only 0.1 units when the "in-use solution" isdiluted by half with water. The solution's pH decreases by only 0.05units per mL of 0.1 N HCl added to the "in-use solution."

Example #3 Split-Chamber System

In this example, a kit is exemplified by the following formulation. Asingle split-chamber bottle is used. The concentrated aromaticdialdehyde solution is in Chamber No. 1, and the buffering system is inChamber No. 2.

    ______________________________________                                        Solution for Chamber 1                                                                        Solution for Chamber 2                                        Ingredient                                                                             Weight Percent                                                                           Ingredient   Weight Percent                               ______________________________________                                        ortho-   25         sodium monobasic                                                                           6                                            phthalaldehyde      phosphate                                                 ethanol  30         sodium dibasic                                                                             18                                                               phosphate                                                 distilled water                                                                        45         distilled water                                                                            75                                                               minor ingredients                                                                          1                                            ______________________________________                                    

Solution 1 of this formulation was prepared by adding the ethanol to thedistilled water. Next, the ortho-phthalaldehyde was added toethanol/water mixture.

Solution 2 was prepared by first heating the distilled water because thephosphate salt dissolves more quickly in heated water than it does incool water. The sodium monobasic phosphate and sodium dibasic phosphateingredients were then added to the heated water. The minor ingredientswere then added. The minor ingredients included 0.5 w/w % of a 1% dye inwater solution and 0.5 w/w % of 1% calcium sequestrant (EDTA) in watersolution.

Example #4 Physical and Chemical Stability of Exemplified Formulations

In this example, the formulations as prepared in Examples 1 and 2 andthe kit as prepared in Example 3 were tested. Physical stability isdefined as no formation of precipitates or phase separation of thesolution, as determined visually. Chemical stability of the aromaticdialdehyde is determined by high performance liquid chromatography.

Both formulations of Examples 1 and 2 showed physical and chemicalstability at 40° C. for a minimum of sixty (60) days. That is, after 60days, neither formulation showed the formation of a precipitate or phaseseparation nor a loss of the aromatic dialdehyde in excess of 15% of thetotal amount initially present.

The kit of Example 3 showed physical and chemical stability at 40° C.for a minimum of thirty (30) days. After 30 days, the kit did show theformation of a precipitate or phase separation nor a loss of thearomatic dialdehyde in excess of 15% of the total amount initiallypresent The kit was not tested beyond thirty days. The kit is expectedto have continued physical and chemical stability beyond sixty (60) daysbecause the solvent and buffering systems are maintained in separatesolutions.

At 4° C., both formulations of Examples 1 and 2 and the kit of Example 3demonstrated physical and chemical stability in excess of two (2) weeks.

The preferred embodiments and examples are given to illustrate the scopeand spirit of the present invention. The embodiments and examples hereinwill make apparent to those skilled in the art other embodiments andexamples. These other embodiments and examples are within the scope ofthe present invention. Thus, the scope of the invention should bedetermined by the appended claims and their legal equivalents, ratherthan by the examples given herein.

What is claimed is:
 1. A disinfecting and sterilizing concentratecomprising:(a) an aromatic dialdehyde present in a concentration greaterthan 5 w/w %, (b) a water miscible solvent, (c) a buffering salt, and(d) a stabilizer to physically stabilize the buffering salt when thebuffering salt and the water miscible solvent are admixed.
 2. Thedisinfecting and sterilizing concentrate of claim 1, wherein(a) thearomatic dialdehyde is selected from the group consisting ofortho-phthalaldehyde, isophthalaldehyde, and terephthalaldehyde.
 3. Thedisinfecting and sterilizing concentrate of claim 1, wherein(b) thesolvent is selected from the group consisting of ethanol, methanol,1,4-butanediol, ethylene glycol, propylene glycol, tetrahydrofuran,isopropanol, polyols, dimethylsulfoxide, and dioxane.
 4. Thedisinfecting and sterilizing concentrate of claim 1, wherein(c) thebuffering salt is selected from the group consisting of boricacid/sodium borate, maleic acid/sodium maleate, monobasicphosphate/dibasic phosphate, and citric acid/sodium citrate.
 5. Thedisinfecting and sterilizing concentrate of claim 4, whereinthestabilizer is a polyol.
 6. The disinfecting and sterilizing concentrateof claim 1, further comprising(e) at least one minor ingredient selectedfrom the group consisting of dyes, chelants, and builders.
 7. Thedisinfecting and sterilizing concentrate of claim
 5. 8. The disinfectingand sterilizing concentrate of claim 1, wherein(a) the aromaticdialdehyde is present in a concentration greater than 5 w/w % up toabout 30 w/w %, (b) the solvent present in a concentration ranging fromabout 1 w/w % to about 60 w/w %, and (c) the buffering salt is presentin a concentration ranging from about 0.5 w/w % to about 25 w/w %. 9.The disinfecting and sterilizing concentrate of claim 8, comprising(d) astabilizer present in a concentration up to about 50 w/w %.
 10. Thedisinfecting and sterilizing concentrate of claim 1, wherein(a) thearomatic dialdehyde is present in a concentration greater than 5 w/w %up to about 25 w/w %, (b) the solvent is present in a concentrationranging from about 5 w/w % to about 50 w/w %, and (c) the buffering saltis present in a concentration ranging from about 1 w/w % to about 20 w/w%.
 11. The disinfecting and sterilizing concentrate of claim 10,comprising(d) a stabilizer present in a concentration up to about 45 w/w%.
 12. The disinfecting and sterilizing concentrate of claim 1wherein(a) the aromatic dialdehyde is present in a concentration rangingfrom about 10 w/w % to about 20 w/w %, (b) the solvent is present in aconcentration ranging from about 10 w/w % to about 45 w/w %, and (c) thebuffering salt is present in a concentration ranging from about 1 w/w %to about 15 w/w %.
 13. The disinfecting and sterilizing concentrate ofclaim 12, comprising(d) a stabilizer present in a concentration up to 40w/w %.
 14. A method for making a disinfecting and sterilizingconcentrate comprising:(i) mixing an amount of an aromatic dialdehydegreater than 5 w/w % with a water miscible solvent, (ii) admixing abuffering salt, and (iii) admixing a stabilizer which physicallystabilizes the buffering salt when the buffering salt and the watermiscible solvent are admixed.
 15. The method of claim 13, furthercomprising(iv) admixing at least one minor ingredient selected from thegroup consisting of dyes, chelants, and builders.
 16. A disinfecting andsterilizing concentrate prepared in accordance with the method of claim14.
 17. A disinfecting and sterilizing concentrate prepared inaccordance with the method of claim 15.